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Why do mitochondria produce more ROS when we age?

为什么随着年龄的增长，线粒体会产生更多的 ROS？

基本信息

批准号：
BB/W006774/1
负责人：
Alberto Sanz Montero
金额：
$ 56.95万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FW006774%2F1
关键词：
Why do mitochondria produce more

项目摘要

An ever-increasing ageing population is the most critical challenge that we will face in this century. Ageing is a health and a socio-economic problem that will determine future political decisions. Societies are dedicating a growing number of public and private resources to the care of the elderly. Losing the ability to have an active and independent life is found to be a main concern amongst the elderly in opinion polls. This problem is aggravated by the absence of a global strategy to address ageing as a single ailment rather than as unconnected individual age-associated diseases. In order to make progress, we need to understand the fundamental causes that drive ageing and identify and implement strategies that target these causes. We must pinpoint and investigate the root causes of ageing, generate appropriate animal models to test hypotheses rigorously and translate these findings into clinical studies in humans. This proposal will generate direct knowledge about how and why we age and interventions that extend animal lifespan. In the past, we and others have shown that the accumulation of defective mitochondria is a hallmark of ageing that is conserved across evolution. Mitochondria are central to cellular energy metabolism. When they are dysfunctional, energy production is interrupted, and cell homeostasis is lost. Accordingly, ageing is characterised by a loss in cellular power. Over the last ten years, we have learned a significant amount about the negative consequences of carrying dysfunctional mitochondria. For example, free radicals produced as toxic metabolic by-products cause cellular damage and are associated with many age-related diseases such as Alzheimer's and Parkinson's diseases. However, it is still unknown why, as we age, mitochondria produce less energy and more toxins. This project will fill this gap in our knowledge by determining why and how dysfunctional mitochondria accumulate during ageing. We will take advantage of the fruit fly's short lifespan and powerful genetics to study how old mitochondria produce free radicals that damage the cell. We will begin by investigating where and at what level free radicals are produced in normal conditions and under stress. Next, we will investigate why defective mitochondria accumulate. We will employ state-of-the-art technology to manipulate the epigenome. The epigenome is the "instruction manual" that reads the information stored in the genome. During ageing, this "manual" is damaged, and cells lose their ability to interpret the genetic code correctly. Finally, we will use this new knowledge to develop innovative strategies to prevent, delay or reverse the accumulation of defective mitochondria, asking whether this is sufficient to extend fly lifespan. The primary goal is to understand what is required for the prevention, delay and reversal of ageing in humans.

人口不断老化，是我们在本世纪所面对的最严峻挑战。老龄化是一个健康和社会经济问题，将决定未来的政治决定。社会正在投入越来越多的公共和私人资源来照顾老年人。在民意调查中，老年人主要关注的问题是丧失积极和独立生活的能力。由于缺乏一项全球战略，将老龄问题作为一种单一的疾病而不是作为与年龄有关的互不相关的个别疾病来处理，这一问题更加严重。为了取得进展，我们需要了解导致老龄化的根本原因，并确定和实施针对这些原因的战略。我们必须查明和调查衰老的根本原因，建立适当的动物模型来严格检验假设，并将这些发现转化为人类的临床研究。这一提议将产生关于我们如何以及为什么衰老的直接知识，以及延长动物寿命的干预措施。在过去，我们和其他人已经证明，有缺陷的线粒体的积累是衰老的标志，在进化过程中是保守的。线粒体是细胞能量代谢的中心。当它们功能失调时，能量生产中断，细胞内稳态丧失。因此，衰老的特征在于细胞能量的损失。在过去的十年里，我们已经了解了大量关于携带功能失调的线粒体的负面后果。例如，作为有毒代谢副产物产生的自由基会导致细胞损伤，并与许多与年龄有关的疾病如阿尔茨海默病和帕金森病有关。然而，仍然不知道为什么随着年龄的增长，线粒体产生更少的能量和更多的毒素。该项目将通过确定为什么以及如何在衰老过程中功能失调的线粒体积累来填补我们知识中的这一空白。我们将利用果蝇短暂的寿命和强大的遗传学来研究衰老的线粒体如何产生破坏细胞的自由基。我们将开始研究在正常条件下和压力下，自由基在哪里产生，在什么水平上产生。接下来，我们将研究为什么有缺陷的线粒体积累。我们将采用最先进的技术来操纵表观基因组。表观基因组是读取存储在基因组中的信息的“指令手册”。在衰老过程中，这种“手册”被破坏，细胞失去了正确解释遗传密码的能力。最后，我们将利用这些新知识来开发创新策略，以防止，延迟或逆转有缺陷的线粒体的积累，并询问这是否足以延长苍蝇的寿命。主要目标是了解预防、延缓和逆转人类衰老所需的条件。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

How the Disruption of Mitochondrial Redox Signalling Contributes to Ageing.

线粒体氧化还原信号的破坏如何导致衰老。

DOI：
10.3390/antiox12040831
发表时间：
2023-03-29
期刊：
ANTIOXIDANTS
影响因子：
7
作者：
Castejon-Vega, Beatriz;Cordero, Mario D. D.;Sanz, Alberto
通讯作者：
Sanz, Alberto

Developmental mitochondrial Complex I activity determines lifespan

DOI：
10.1101/2023.06.21.545894
发表时间：
2023-06
期刊：
bioRxiv
影响因子：
0
作者：
Rhoda Stefanatos;Fiona Robertson;A. Uribe;Yizhou Yu;Kevin Myers;Beatriz Castejón-Vega;T. Kataura;L. Martins;V. Korolchuk;Oliver D. K. Maddocks;A. Sanz
通讯作者：
Rhoda Stefanatos;Fiona Robertson;A. Uribe;Yizhou Yu;Kevin Myers;Beatriz Castejón-Vega;T. Kataura;L. Martins;V. Korolchuk;Oliver D. K. Maddocks;A. Sanz

Mitochondrial redox signaling: a key player in aging and disease.